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kynurenine pathway

Function: - metabolic pathway resulting in production of NAD+ - intermediary metabolites include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, & 3-hydroxykynurenine [1] * illustrations of the Kynurenine pathway may be found in [1,2] * also see figure Biochemistry: - kynurenine pathway 1 - enzyme: indoleamine-2,3-dioxygenase - substrate: tryptophan + O2 - product: N-formylkynurenine - kynurenine pathway 1b - enzyme: tryptophan-2,3-dioxygenase - substrate: tryptophan + O2 - product: N-formylkynurenine - within hepatocyte - kynurenine pathway 2 - enzyme: formamidase - substrate: N-formylkynurenine + H2O - product: kynurenine + formate - kynurenine pathway 3 - enzyme: kynurenine aminotransferase - substrate: kynurenine - product: kynurenate - kynurenine pathway 3b - enzyme: alcohol oxidoreductase - substrate: kynurenate - product: quinaldate - kynurenine pathway 4 - enzyme: kynureninase - substrate: kynurenine + H2O - product: anthranilate + alanine - kynurenine pathway 5 - enzyme: Kynurenine-3-monooxygenase - substrate: kynurenine + O2 + NADPH - product: 3-hydroxykynurenine + H2O + NADP - kynurenine pathway 5b - enzyme: hydroxylase - substrate: anthranilate + O2 + NADPH - product: 3-hydroxyanthranilate + H2O + NADP - occurs in brain - kynurenine pathway 6 - enzyme: kynurenine aminotransferase - substrate: 3-hydroxykynurenine - product: xanthurenate - kynurenine pathway 6b - enzyme: alcohol oxidoreductase - substrate: xanthurenate - product: 8-hydroxyquinaldate - kynurenine pathway 7 - enzyme: kynureninase - substrate: 3-hydroxykynurenine + H2O - product: 3-hydroxyanthranilate + alanine - kynurenine pathway 8 - enzyme: 3-hydroxyanthranilate oxygenase - substrate: 3-hydroxyanthranilate + O2 - product: 2-acroleyl-3-aminofumarate - kynurenine pathway 8b - enzyme: oxidoreductase - substrate: 3-hydroxyanthranilate - product: 2-aminophenol - kynurenine pathway 9a - enzyme: picolinate carboxylase - substrate: 2-acroleyl-3-aminofumarate - product: 2-aminomuconic semialdehyde - kynurenine pathway 9b - substrate: 2-aminomuconic semialdehyde - product: picolinate - spontaneous - kynurenine pathway 9c - enzyme: aldehyde oxidoreductase - substrate: 2-aminomuconic semialdehyde - product: 2-aminomuconate - kynurenine pathway 9d - enzyme: aminotransferase - substrate: 2-aminomuconate - product: alpha-ketoadipate - kynurenine pathway 9e - enzyme: transferase - substrate: alpha-ketoadipate + Coenzyme-A - product: glutaryl-CoA + CO2 - kynurenine pathway 9f - enzyme: oxidoreductase - substrate: glutaryl-CoA + Coenzyme-A - product: 2 acetyl-CoA + CO2 - kynurenine pathway 10 - substrate: 2-acroleyl-3-aminofumarate - product: quinolinate - spontaneous - kynurenine pathway 11 - enzyme: quinolinate phosphoribosyltransferase - substrate: quinolinate - product: quinolinate ribonucleotide - kynurenine pathway 12 - substrate: quinolinate ribonucleotide - product: nicotinate ribonucleotide

Related

kynurenine

General

biosynthetic pathway or anabolic pathway tryptophan metabolism

Properties

EVENTS: enzymatic reaction ENZYME: indoleamine-2,3-dioxygenase COMPARTMENT: cytoplasm CELL: unspecified cell type WITHIN: brain lung kidney intestine stomach placenta MOTIF: active site SUBSTRATE: tryptophan O2 PRODUCT: N-formyl kynurenine TAG: KYNURENINE-PATHWAY-1 enzymatic reaction ENZYME: tryptophan-2,3-dioxygenase COMPARTMENT: cytoplasm CELL: hepatocyte MOTIF: Ser phosphorylation site {S155} SUBSTRATE: tryptophan COMPARTMENT: cytoplasm CELL: hepatocyte O2 PRODUCT: N-formyl kynurenine COMPARTMENT: cytoplasm CELL: hepatocyte TAG: KYNURENINE-PATHWAY-1B enzymatic reaction ENZYME: formamidase MOTIF: active site SUBSTRATE: N-formyl kynurenine H2O PRODUCT: kynurenine formate TAG: KYNURENINE-PATHWAY-2 enzymatic reaction ENZYME: kynurenine aminotransferase MOTIF: cofactor-binding site COFACTOR-BOUND: pyridoxal phosphate SUBSTRATE: kynurenine PRODUCT: kynurenate TAG: KYNURENINE-PATHWAY-3 enzymatic reaction ENZYME: alcohol oxidoreductase MOTIF: active site SUBSTRATE: kynurenate PRODUCT: quinaldate TAG: KYNURENINE-PATHWAY-3B enzymatic reaction ENZYME: kynureninase COMPARTMENT: cytoplasm MOTIF: acetylation site SITE: 1-1 EFFECTOR-BOUND: acetyl cofactor-binding site [276-276] FOR-BINDING-OF: pyridoxal phosphate SUBSTRATE: kynurenine H2O PRODUCT: anthranilate alanine TAG: KYNURENINE-PATHWAY-4 enzymatic reaction ENZYME: kynurenine 3-monooxygenase COMPARTMENT: mitochondria MOTIF: transmembrane domain {385-404} MOTIF: Thr phosphorylation site {T399} transmembrane domain {425-445} SUBSTRATE: kynurenine O2 NADPH PRODUCT: 3-hydroxykynurenine H2O NADP TAG: KYNURENINE-PATHWAY-5 enzymatic reaction ENZYME: hydroxylase COMPARTMENT: intracellular compartment CELL: unspecified cell type WITHIN: brain MOTIF: active site SUBSTRATE: anthranilate O2 NADPH PRODUCT: 3-hydroxyanthranilate H2O NADP TAG: KYNURENINE-PATHWAY-5B enzymatic reaction ENZYME: kynurenine aminotransferase MOTIF: cofactor-binding site COFACTOR-BOUND: pyridoxal phosphate SUBSTRATE: 3-hydroxykynurenine PRODUCT: xanthurenate TAG: KYNURENINE-PATHWAY-6 enzymatic reaction ENZYME: alcohol oxidoreductase MOTIF: active site SUBSTRATE: xanthurenate PRODUCT: 8-OH quinaldate TAG: KYNURENINE-PATHWAY-6B enzymatic reaction ENZYME: kynureninase COMPARTMENT: cytoplasm MOTIF: acetylation site SITE: 1-1 EFFECTOR-BOUND: acetyl cofactor-binding site [276-276] FOR-BINDING-OF: pyridoxal phosphate SUBSTRATE: 3-hydroxykynurenine H2O PRODUCT: 3-hydroxyanthranilate alanine TAG: KYNURENINE-PATHWAY-7 enzymatic reaction ENZYME: 3-OH anthranilate oxygenase COMPARTMENT: cytoplasm MOTIF: binding site SITE: 43-43 FOR-BINDING-OF: Dioxygen Iron [Fe]-binding site SITE: 47-47 Iron [Fe]-binding site SITE: 53-53 MOTIF: binding site SITE: 53-53 FOR-BINDING-OF: Substrate Iron [Fe]-binding site SITE: 91-91 binding site SITE: 95-95 FOR-BINDING-OF: Substrate binding site SITE: 105-105 FOR-BINDING-OF: Substrate SUBSTRATE: 3-hydroxyanthranilate O2 PRODUCT: 2-acroleyl-3-amino fumarate TAG: KYNURENINE-PATHWAY-8 enzymatic reaction ENZYME: oxidoreductase MOTIF: active site SUBSTRATE: 3-hydroxyanthranilate PRODUCT: 2-aminophenol TAG: KYNURENINE-PATHWAY-8B enzymatic reaction ENZYME: picolinate carboxylase MOTIF: active site SUBSTRATE: 2-acroleyl-3-amino fumarate PRODUCT: 2-aminomuconic semialdehyde TAG: KYNURENINE-PATHWAY-9A chemical reaction SUBSTRATE: 2-aminomuconic semialdehyde PRODUCT: picolinate TAG: KYNURENINE-PATHWAY-9B enzymatic reaction ENZYME: aldehyde oxidoreductase MOTIF: active site SUBSTRATE: 2-aminomuconic semialdehyde PRODUCT: 2-amino muconate TAG: KYNURENINE-PATHWAY-9C enzymatic reaction ENZYME: aminotransferase MOTIF: cofactor-binding site COFACTOR-BOUND: pyridoxal phosphate SUBSTRATE: 2-amino muconate PRODUCT: alpha-ketoadipate TAG: KYNURENINE-PATHWAY-9D enzymatic reaction ENZYME: transferase MOTIF: active site SUBSTRATE: alpha-ketoadipate coenzyme A PRODUCT: glutaryl CoA CO2 TAG: KYNURENINE-PATHWAY-9E enzymatic reaction ENZYME: oxidoreductase MOTIF: active site SUBSTRATE: glutaryl CoA coenzyme A PRODUCT: acetyl-CoA (2) CO2 TAG: KYNURENINE-PATHWAY-9F chemical reaction SUBSTRATE: 2-acroleyl-3-amino fumarate PRODUCT: quinolinate TAG: KYNURENINE-PATHWAY-10 enzymatic reaction ENZYME: quinolinate phosphoribosyltransferase CONFIGURATION: pentamer STATE: active state MOTIF: active site allosteric site Mg+2-binding site EFFECTOR-BOUND: Mg+2 SUBSTRATE: quinolinate PRODUCT: quinolinate ribonucleotide TAG: KYNURENINE-PATHWAY-11 chemical reaction SUBSTRATE: quinolinate ribonucleotide PRODUCT: nicotinate ribonucleotide TAG: KYNURENINE-PATHWAY-12

References

  1. Wikipedia: Kynurenine_pathway https://en.wikipedia.org/wiki/Kynurenine_pathway
  2. Savitz J The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020 Jan;25(1):131-147 PMID: 30980044 PMCID: PMC6790159 Free PMC article
  3. Majewski M, Kozlowska A, Thoene M, Lepiarczyk E, Grzegorzewski WJ. Overview of the role of vitamins and minerals on the kynurenine pathway in health and disease. J Physiol Pharmacol. 2016 Feb;67(1):3-19. PMID: 27010891 Review.
  4. Castro-Portuguez R, Sutphin GL. Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan. Exp Gerontol. 2020 Apr;132:110841. PMID: 31954874 Free PMC article. Review.
  5. Maddison DC, Giorgini F. The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol. 2015 Apr;40:134-41. PMID: 25773161 Review.
  6. Lovelace MD, Varney B, Sundaram G et al Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology. 2017 Jan;112(Pt B):373-388. PMID: 26995730 Review.
  7. Boros FA, Bohar Z, Vecsei L. Genetic alterations affecting the genes encoding the enzymes of the kynurenine pathway and their association with human diseases. Mutat Res. 2018 Apr-Jun;776:32-45. PMID: 29807576 Review.
  8. Eastman & Guilarte J Nutr Biochem 3:618 1992
  9. Principles of Biochemistry 6th ed., White, Handler, Smith, Hill, & Lehman (eds.) McGraw-Hill, NY 1978, pg 751